Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the Renin-angiotensin system plays a central role in the regulation of normal blood pressure and seems to be critically involved in hypertension development and maintenance as well as congestive heart failure.
• Angiotensin II (A II), is an octapeptide hormone produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs. It is the end product of the renin-angiotensin system (RAS) and is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes.
• ACE angiotensin converting enzyme
• non-peptide compounds have been described as A II antagonists.
• Illustrative of such compounds are those disclosed in U.S. Pat. Nos. 4,207,324; 4,340,598; 4,576,958; 4,582,847; and 4,880,804 and in European Patent Applications 028,834; 234,637; 253,310; and 291,969; and articles by A. T. Chiu, et al. [Eur. J. Pharm. Exp. Therap, 157, 13-21 (1988)] and by P. C. Wong, et al. [J. Pharm. Exp. Therap, 247, 1-7 (1988)]. All of the U.S.
• Patents European Patent Applications 028,834 and 253,310 and the two articles disclose substituted imidazole compounds which are generally bonded through a lower alkyl bridge to a substituted phenyl.
• European Patent Application 245,637 discloses derivatives of 4,5,6,7-tetrahydro-2H-imidazo[4,5-c]-pyridine-6-carboxylic acid and analogs thereof as antihypertensive agents.
• This invention is directed to substituted heterocycles attached through a methylene bridge to novel substituted phenylthiophene or phenylfuran derivative to give compounds of the Formula I, which are angiotensin II antagonists and are useful in the treatment of hypertension and congestive heart failure.
• the compounds of the invention are useful as ocular antihypertensives.
• the compounds of this invention contain a heterocyclic moiety which is substituted at the specified positions and to which is methylene bridge connecting a novel substituted phenylthiophene or phenylfuran group as defined by the lower portion of Formula I, is attached.
• pharmaceutically acceptable compositions of these novel compounds as the sole therapeutically active ingredient and in combination with diuretics and other antihypertensive agents, including beta blockers, angiotensin converting enzyme inhibitors, calcium channel blockers or a combination thereof are disclosed and claimed. Further, methods of treating hypertension and congestive heart failure are described and claimed.
• the compounds of this invention have central nervous system (CNS) activity. They are useful in the treatment of cognitive dysfunctions including Alzheimer's disease, amnesia and senile dementia. These compounds also have anxiolytic and antidepressant properties and are therefore, useful in the relief of symptoms of anxiety and tension and in the treatment of patients with depressed or dysphoric mental states.
• CNS central nervous system
• these compounds exhibit antidopaminergic properties and are thus useful to treat disorders that involve dopamine dysfunction such as schizophrenia.
• the compounds of this invention are especially useful in the treatment of these conditions in patients who are also hypertensive or have a congestive heart failure condition.
• R 1 is: (a) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of:
• aryl wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
• heteroaryl wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the heteroaryl is unsubstituted, monosubstituted or disubstituted with substituents selected from the group consisting of:
• n 0 to 2;
• s is 0 to 5;
• J 1 is (a)--C( ⁇ M)--, (b) J 1 and L are connected together to form a 6-carbon aromatic ring substituted with R 7a , R 7b , R 8a and R 8b or (c) J 1 and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom not at J 1 , substituted with R 7a , R 8a l and R 8b ;
• K 1 is (a)--C( ⁇ M)--, (b) K 1 and L are connected together to form a 6-carbon aromatic ring substituted with R 7a , R 7b , R 8a and R 8b , or (c) K 1 and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom, substituted on the carbon atoms with R 7a , R 8a and R 8b ;
• one of a 1 or b 1 is a double bond in structures Ia provided that when J 1 is --C( ⁇ M)-- then b 1 is a double bond and when K 1 is --C( ⁇ M)-- then a 1 is a double bond;
• L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom
• J 2 is (a)--C( ⁇ M)--, or (b) --C(R 17 )--;
• K 2 is (a)--C( ⁇ M)--, or (b)--C(R 17 )--, provided that one and only one of J 2 and K 2 is --C( ⁇ M)--;
• one of a 2 or b 2 is a double bond in structure Ic provided that when J 2 is --C( ⁇ M)-- then b 2 is a double bond and when K 2 is --C( ⁇ M)-- then a 2 is a double bond.
• M is O, S or NR 15 ;
• R 2 is:
• R 2a is:
• R 2b is:
• R 2c is:
• R 7a and R 7b are independently
• R 7a and R 7b when R 7a and R 7b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring;
• R 8a and R 8b are independently
• (d) (C 1 -C 6 )-alkyl which is unsubstituted or substituted with a substituent selected from the group consisting of: --CON(R 2a ) 2 , -heteroaryl, --S(O) n R 21 , -tetrazol-5-yl, --CONHSO 2 R 21 , --SO 2 NH-heteroaryl, --SO 2 NHCOR 21 , --PO(OR 2 ) 2 , --PO(OR 2a ) 2 , --SO 2 NH--CN, --NR 2a COOR 21 , --OH, --NH 2 , guanidino, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylamino, (C 1 -C 4 )-dialkylamino, --COOR 2a , --CONHR 2a , --O--COR 2a , aryl,
• --X 1 --X 2 --X 3 --X 4 -- is: (a) --Y--CR 11 --CR 12 --CZ--,
• Y is: O, S, SO, or SO 2 ;
• R 9 and R 10 are each independently:
• aryl wherein aryl is phenyl or naphthyl, unsubstituted or substituted with one or two substituents selected from the group consisting of: Cl, Br, I, F, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, NO 2 , CF 3 , (C 1 -C 4 )-alkylthio, OH, NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 , --CO 2 H, or --CO 2 --(C 1 -C 4 )-alkyl, or
• R 11 and R 12 are independently:
• R 14 is (a) aryl
• aryl which is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: Cl, Br, I, F --O--(C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl, --NO 2 , --CF 3 , --SO 2 NR 2 R 2a , --S--(C 1 -C 4 )-alkyl, --OH, --NH 2 , (C 3 -C 7 )-cycloakyl, (C 3 -C 10 )-alkenyl;
• an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6 membered ring which can contain one or two heteroatoms selected from the group consisting of N, O, S, and wherein the substituents are members selected from the group consisting of --OH, --SH, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, --CF 3 , Cl, Br, I, F, or NO 2 ;
• V and W are each independently selected from:
• M 1 is M or --C(O)--;
• z is 0 or 1;
• r and t are 0 to 2;
• R 17 and R 18 are each independently selected from:
• heteroaryl wherein heteroaryl is a 5 or 6 membered aromatic ring containing one or two heteroatoms selected from the group consisting of O, N, or S,
• R 19 is:
• R 20 is --CN, --NO 2 , --CO 2 R 2a , or --CF 3 ;
• R 21 is:
• R 1 is:
• J 1 is (a)--C( ⁇ M)--, (b) J 1 and L are connected together to form a 6-carbon aromatic ring substituted with R 7a , R 7b , R 8a and R 8b or (c) J 1 and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom not at J 1 , substituted with R 7a , R 8a and R 8b ;
• K 1 is (a)--C( ⁇ M)--, or (b) K 1 and L are connected together to form a 6-carbon aromatic ring substituted with R 7a , R 7b , R 8a and R 8b , or (c) K 1 and L are connected together to form a six-membered aromatic ring containing one nitrogen atom substituted with R 7a , R 8a and R 8b provided that one and only one of J 1 and K 1 is --C( ⁇ M)--;
• one of a 1 or b 1 is a double bond in structure Ia provided that when J 1 is --C( ⁇ M)-- then b 1 is a double bond and when K 1 is --C( ⁇ M)-- then a 1 is a double bond;
• L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom
• J 2 is (a)--C( ⁇ M)--, or (b) --C(R 17 )--;
• K 2 is (a)--C( ⁇ M)--, or (b)--C(R 17 )--, provided that one and only one of J 2 and K 2 is --C( ⁇ M)--;
• one of a 2 or b 2 is a double bond in structure Ic provided that when J 2 is --C( ⁇ M)-- then b 2 is a double bond and when K 2 is --( ⁇ M)-- then a 2 is a double bond.
• M is O, S or NR 15 ;
• R 2 is:
• R 2a is:
• R 2b is:
• R 2c is:
• R 7a and R 7b are independently
• R 7a and R 7b when R 7a and R 7b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring;
• R 8a and R 8b are independently
• (d) (C 1 -C 6 )-alkyl is unsubstituted or substituted with a substituent selected from the group consisting of: --CON(R 2a ) 2 , -heteroaryl, --S(O) x --R 21 , -tetrazol-5-yl, --CONHSO 2 R 21 , --SO 2 NH-heteroaryl, --SO 2 NHCOR 21 , --PO(OR 2 ) 2 , --PO(OR 2a ) 2 , --SO 2 NH--CN, --NR 2a COOR 21 , --OH, --NH 2 , guanidino, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-alkylamino, (C 1 -C 4 )-dialkylamino, --COOR 2a , --CONHR 2a , --O--COR 2a , aryl,
• --X 1 --X 2 --X 3 --X 4 -- is: (a) --Y--CR 11 --CR 12 --CZ--,
• Y is: O, S, SO, or SO 2 ;
• R 9 and R 10 are each independently:
• aryl wherein aryl is phenyl or naphthyl, unsubstituted or substituted with one or two substituents selected from the group consisting of: Cl, Br, I, F, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, NO 2 , CF 3 , (C 1 -C 4 )-alkylthio, OH, NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 , --CO 2 H, or --CO 2 -(C 1 -C 4 -alkyl, or
• R 11 and R 12 are independently:
• heteroaryl is an unsubstituted, monosubstituted or disubstituted five or six membered aromatic ring which can optionally contain from 1 to 3 heteroatoms selected from the group consisting of O, N or S and wherein the substituents are members selected from the group consisting of --OH, --SH, --(C 1 -C 4 )-alkyl, --(C 1 -C 4 )-alkoxy, --CF 3 , Cl, Br, F, I, --NO 2 , --CO 2 H, --CO 2 --C 1 -C 4 -alkyl, --NH 2 , NH[(C 1 -C 4 )-alkyl] and --N[(C 1 -C 4 -alkyl] 2 ,
• R 15 is:
• aryl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of Cl, Br, I, F, --O--(C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl, --NO 2 , --CF 3 , --SO 2 NR 2 R 2a , --S--(C 1 -C 4 )-alkyl, --OH, --NH 2 , (C 3 -C 7 )-cycloalkyl, (C 3 -C 10 )-alkenyl;
• R 16 is:
• V and W are selected from:
• R 17 and R 18 are independently
• heteroaryl wherein heteroaryl is a 5 or 6 membered aromatic ring containing one or two heteroatoms selected from the group consisting of O, N, or S;
• R 21 is:
• R 1 is:
• J 1 and L are connected together to form a 6-carbon aromatic ring substituted with R 7a , R 7b , R 8a and R 8b ; or J 1 and L are connected together to form a 6 -membered aromatic ring containing one nitrogen atom not at J 1 , substituted with R 7a , R 8a and R 8b ;
• K 1 is --C( ⁇ M)--
• a 1 is a double bond
• L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom
• J 2 is --C(R 17 )--;
• K 2 is --C( ⁇ M)--
• a 2 is a double bond
• M is O, or NR 15 ;
• R 2 is:
• R 2a is:
• R 2b is:
• R 2c is:
• R 7a and R 7b are independently:
• R 7a and R 7b when R 7a and R 7b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring;
• R 8a and R 8b are independently:
• --X 1 --X 2 --X 3 --X 4 -- is: (a) --Y--CR 11 --CR 11 --CR 12 --CZ--,
• Y is: O or S
• R 9 and R 10 are each independently:
• aryl wherein aryl is phenyl or naphthyl, unsubstituted or substituted with one or two substituents selected from the group consisting of: Cl, Br, I, F, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, NO 2 , CF 3 , (C 1 -C 4 )-alkylthio, OH, NH 2 , --NH[(C 1 -C 4 )-alkyl], --N[(C 1 -C 4 )-alkyl] 2 , --CO 2 H, or --CO 2 -(C 1 -C 4 )-alkyl, or
• R 11 and R 12 are independently:
• R 15 is:
• aryl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of: Cl, Br, I, F --O--(C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyl, --NO 2 , --CF 3 , --SO 2 NR 2 R 2a , --S--(C 1 -C 4 )-alkyl, --OH, --NH 2 , (C 3 -C 7 )-cycloalkyl, (C 3 -C 10 )-alkenyl;
• an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6 membered ring which can contain one or two heteroatoms selected from the group consisting of N, O, S, and wherein the substituents are members selected from the group consisting of: --OH, --SH, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyloxy --CF 3 , Cl, Br, I, F, or NO 2 ;
• V and W are selected from:
• R 17 and R 18 are independently
• R 21 is:
• a class within the embodiment is when the structural formula is: ##STR14##
• a subclass within the embodiment is when the structural formula is: ##STR15## or a pharmaceutically acceptable salt thereof, wherein the substituents are as defined above.
• a subclass within this class is when the structural formula is: ##STR16## wherein R 1 is: ethyl, n-propyl, n-butyl or pentyl;
• R 2c is: H, COCH 3 , CO 2 Me CO 2 Et, CONHCH 3 , CON[CH 3 ] 2 , COphenyl, CO-4-pyridinyl, CO 2 -n-butyl, CO-cyclopropyl, SO 2 -isopropyl, CONH-n-propyl, or ##STR17##
• R 8b is: N(n-butyl)CO-phenyl,
• R 11 is: H or R 11 and R 12 can joined to form an phenyl ring;
• R 12 is: H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, --CH 2 -aryl, O(CH 2 ) n+1 O(CH 2 ) s CH 3 , (CH 2 ) n+1 O(CH 2 ) s (CH 3 , or CH 2 N[CH 2 CH 2 ] 2 O;
• Y is: O, or S
• Another subclass of within this class is when the structural formula is: ##STR19## or a pharmaceutically acceptable salt thereof.
• Another subclass of within this class is when the structural formula is: ##STR20## or a pharmaceutically acceptable salt thereof.
• Another class within this embodiment is when the structural formula is: ##STR21## or a pharmaceutically acceptable salt thereof.
• R 1 is: ethyl, n-propyl, n-butyl;
• R 16 is:
• R 11 is: H or R 11 and R 12 can joined to form an phenyl ring;
• R 12 is: H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, --CH 2 -aryl, O(CH 2 ) n+1 O(CH 2 ) s CH 3 , (CH 2 ) n+1 O(CH 2 ) s CH 3 , or CH 2 N[CH 2 CH 2 ] 2 O;
• Y is: O, or S
• Another class within this embodiment is when the structural formula is: ##STR23## or a pharmaceutically acceptable salt thereof.
• R 1 is: ethyl, n-propyl, n-butyl,
• R 17 and R 18 are independently:
• R 11 is: H or R 11 and R 12 can joined to form an phenyl ring;
• R 12 is: H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkoxy, --CH 2 -aryl, O(CH 2 ) n+1 O(CH 2 ) s CH 3 , (CH 2 ) n+1 O(CH 2 ) s CH 3 , or CH 2 N[CH 2 CH 2 ] 2 O;
• Y is: O, or S
• alkyl substituents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl, ethyl, isopropyl, isobutyl, neopentyl, isopentyl, etc.
• alkenyl and alkynyl substituents denote alkyl groups as described above which are modified so that each contains a carbon to carbon double bond or triple bond, respectively, such as vinyl, allyl and 2-butenyl.
• Cycloalkyl denotes rings composed of 3 to 8 methylene groups, each which may be substituted or unsubstituted with other hydrocarbon substituents, and include for example cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
• the alkoxy substituent represents an alkyl group as described above attached through an oxygen bridge.
• aryl substituent recited above represents phenyl or naphthyl.
• heteroaryl substituent recited above represents any 5- or 6-membered aromatic ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, for example, pyridyl, thienyl, furyl, imidazolyl, and thiazolyl.
• antagonists of Formula I consist of a heterocyclic component designated above by formulas Ia through Ic and a substituted benzyl substitutent which is attached to the heterocyclic component at a nitrogen atom.
• two generally applicable approaches to antagonists of formula I are these:
• a heterocycle, designated above with Formulas Ia through Ic is prepared as described in PART I below. Then the heterocycle is alkylated at a nitrogen atom with a substituted benzyl halide or pseudohalide giving an alkylated heterocycle in the Schemes below, this alkylating agent is often designated as "Ar--CH 2 Q where Q is a halide (--Cl,Br,I) or pseudohalide (--OMs, OTs, OTf). In some cases, alkylation may take place at more than one nitrogen atom of the heterocycle, and in these cases, separation by fractional crystallization or by chromatographic methods may be necessary for isolation of the desired product.
• the alkylation step produces a fully-assembled antagonist of Formula I, except that functional groups in the alkylating agent or in the heterocycle may be present in protected form and require deprotection steps to be carried out to complete the synthesis.
• the alkylation is carried out with a substituted benzylic halide or pseudohalide ("Ar--CH 2 Q"), but here the alkylation step is followed by subsequent steps which are required to assemble the substituted benzyl element of the antagonist of Formula I.
• the alkylation steps and subsequent steps used to prepare antagonists of Formula I are described in PART II below.
• An appropriately substituted anthranilonitrile is acylated using the requisite acyl chloride.
• the resulting amide is alkylated with sodium hydride and the appropriate alkyl halide (or pseudohalide).
• the resulting tertiary amide is then rearranged/cyclized with basic hydrogen peroxide 1 .
• 2-Substituted quinazolinones may be prepared from substituted anthranilonitriles as described in the literature and illustrated in Scheme I-2.
• the appropriately substituted anthranilonitrile is acylated using the requisite acyl chloride then cyclized using basic hydrogen peroxide. 1 ##STR27##
• Scheme I-3 shows an alternate preparation of 2-substituted quinazolinones starting with the corresponding anthranilic acid.
• the appropriately substituted anthranilic acid is treated with two equivalents of the requisite acyl chloride in DMF with triethylamine and DMAP at 0° C. This is then heated to 110° C. for two hours after which time excess ammonium carbonate is added. 2 ##STR28##
• Scheme I-4 illustrates the general preparation of 2,3-disubstituted quinazolin-4-(3H)-ones of Formula Ia, wherein E is a single bond and K 1 is --C(O)--.
• An appropriately substituted 2-substituted quinazolinone (see Scheme I-2 or Scheme I-3) is alkylated using sodium hydride and the appropriate alkyl halide (or pseudohalide). This reaction sometimes gives some O-alkylated product, generally less than 20% of the isolated reaction products. ##STR29##
• Schemes I-5, I-6, and I-7 provide an alternate route to compounds of Formula Ia, wherein E is a single bond and K 1 is --C(O)--.
• the necessary alkyl amine may then be prepared from the alkyl halide (or pseudohalide) using the standard literature procedures (Scheme I-6). 5 Then, the amine and the 3,1,4-benzoxazone are heated together to give the desired 2,3-disubstituted quinazolinone 2 (Scheme I-7). ##STR30##
• Substituted 2-alkylthioquinazolin-4(3H)-ones wherein K 1 is --C(O)-- and E is --S-- may be prepared from their corresponding substituted anthranilic acids as shown in Scheme I-8.
• the amine from Scheme I-6 can be converted to its isothiocyanate upon treatment with thiophosgene. This may then be reacted with an appropriately substituted anthranilic acid to give the desired 3-alkyl-2-mercapto-quinazolin-4(3H)-one.
• 6 A second alkylation of the mercapto group then gives the desired 2-alkylthio-3-alkylquinazolin-4(3H)-one. 7 ##STR31##
• 2-alkoxyquinazolin-4(3H)-ones wherein K 1 is --C(O)-- and B is --O-- may be prepared from their corresponding substituted anthranilic acids as shown in Scheme 9. 8 Alkylation with the appropriate alkyl halide according to the methods developed by Lange and Sheibley 9 then gives the final product 17. ##STR32##
• Scheme I-10 illustrates a possible route to the isomeric 1,2-disubstituted quinazolin-4(1H)-ones wherein J 1 is --C(O)-- and wherein E is --S-- or --O--.
• An anthranilonitrile can be acylated with an alkyl haloformate or an alkylthiol haloformate. 10 This may then be deprotonated and alkylated with the appropriate alkyl halide to give the intermediate carbamate nitrile shown. 11 Conversion of the intermediate then could occur when the material is treated with basic hydrogen peroxide to yield the desired product 20. ##STR33##
• Scheme I-11 illustrates the method by which a 2-amino-3-alkylquinazolinone can be made.
• the 2-mercaptoquinazolinone (14) shown in Scheme I-8 can be treated with sulfuryl chloride to give the corresponding 2-chloroquinazolinone.
• Scheme I-12 illustrates the method by which a 2-amino-1-alkylquinazolinone can be made.
• the products from Scheme I-10 can be used as a synthetic intermediate if the initial R 1 is a protecting group such as benzyl or t-butyl. 14
• Deprotection and subjection of the resulting 2-mercapto-1-alkyl-quinazolinone to the same conditions used in Scheme I-11 will result in the formation of the desired 2-amino-1-alkylquinazolin-4(1H)-one.
• the sulfide may be displaced directly by an R 1 amine as shown in Scheme I-13 (R 1 --S-- and R 1 --NH 2 may or may not have the same R 1 ).
• the amine (26) may then be reacted with a variety of reagents known to form derivatives of amines such as alkyl- or aryl-carboxylic acid chlorides, chloroformates, sulfonyl and sulfamoyl chlorides, isocyanates and isothiocyanates.
• Scheme I-14 illustrates the derivatization of amine 26 with a generalized chloroformate to afford substituted carbamates such as 27.
• the acylation of amine 26 with a chloroformate is best carried out in the presence of a strong base such as sodium hydride to deprotonate the amine. This anion then reacts readily with chloroformates to give the substituted carbamates 27.
• the carbamate (27) may be isolated, then deprotonated with lithium bis(trimethylsilyl)amide and alkylated to give the N,O-disubstituted carbamates 28.
• this process may be carried out in one flask by first deprotonating the aniline (i.e. with sodium hydride in DMF), reacting the anion with an acyl halide or chloroformate, then treating the intermediate with an equivalent of a strong base such as lithium bis(trimethylsilyl)amide and finally adding an alkylating agent to obtain 28.
• the carbamoyl-substituted quinazolinones 27 and 28 may be cleanly deprotected under acidic conditions such as trifluoroacetic acid-anisole to afford the heterocycles 29 and 30 respectively.
• Scheme I-15 illustrates the reaction of amine 25 with isocyanates to give disubstituted ureas (31). Tetrasubstituted and trisubstituted ureas such as 34 and 35 may be prepared from the benzyl carbamate 27 as shown in Scheme I-16. Thus, treatment of 27 with the magnesium salt of a secondary amine formed from the secondary amine and methylmagnesium bromide affords the trisubstituted urea 32. Trisubstituted ureas (32) may be N-alkylated by deprotonation of the remaining hydrogen with lithium bis(trimethylsilyl)amide followed by alkylation with an alkyl iodide to give 33.
• the urea-substituted quinzolines 32 and 33 may be cleanly deprotected under acidic conditions such as trifluoroacetic acid-anisole to afford the heterocycles 34 and 35 respectively.
• the amine 26 (Scheme I-14) may be derivatized or converted to other functional groups using chemical procedures well known to those skilled in the art. After the appropriate 6-substituent has been constructed the protecting group may be removed by treatment with trifluoroacetic acid in the presence of anisole as illustrated in Schemes I-14 through I-16. The heterocycles obtained in this manner may be incorporated into Angiotensin II Antagonists of general Formula Ia as described in Part II. ##STR37##
• the compounds of Formula Ib can be prepared by a variety of methods typified by those described below in Schemes I-17 to I-28. General synthetic methods for 2,4,5-trisubstituted-1,2,4-triazolin-3(4H)-ones and -triazolin-3(4H)-thiones are discussed in books or review articles such as:
• the compounds of Formula Ib are constructed in such a way that N 1 and N 2 of the triazole ring are derived from hydrazine or a hydrazine derivative, while N 4 of the triazole and the 4-(arylmethyl) substituent are derived directly or indirectly from a suitably substituted benzylamine (or isocyanate or isothiocyanate) or from a benzyl halide (or methanesulfonate, p-toluenesulfonate, etc.).
• reaction Schemes described below are reasonably general, it will be understood by those skilled in the art of organic synthesis that one or more functional groups present in a given compound of Formula Ib may render the molecule incompatible with a particular synthetic sequence. In such a case an alternative route, an altered order of steps, or a strategy of protection and deprotection may be employed. In all cases the particular reaction conditions (including reagents, solvent, temperature, and time) should be chosen so that they are consistent with the nature of the functionality present in the molecule.
• R 1 and R 16 groups represent functionalized or unfunctionalized alkyl, aryl, heteroaryl, aralkyl, and the like.
• the moiety, R 16 Q represents an alkylating agent in which R 16 is typically a functionalized or unfunctionalized alkyl or aralkyl group, while Q is a leaving group such as chloro, bromo, iodo, methanesulfonate, or p-toluenesulfonate.
• M is O or S.
• the isocyanate 2 itself is obtainable by well-known methods from various sources, including the (arylmethyl)amine (by phosgene treatment), the arylmethyl halide (by treatment with cyanate anion), and the arylacetic acid or derivative (via Curtius rearrangement of the acyl azide). Upon heating in the presence of hydroxide or alkoxide, cyclization of 3 to the triazolinone 4 occurs.
• Reaction Schemes I-17 and I-18 are not suitable for the introduction of most aryl or heteroaryl substituents at N 2 .
• the procedures of Reaction Schemes I-19 to I-22 are especially well suited for the synthesis of compounds of Formula Ib having aryl or heteroaryl substituents at N 2 , since the triazolinone ring is constructed with the N 2 -substituent in place, whereas the N 4 -substituent is introduced subsequently by alkylation.
• Reaction Scheme I-19 presents a route patterned after that reported by K. Yabutani, K. Taninaka, M. Kajioka, K. Takagi, H. Matsui, K. Sutoh, and M.
• N-carbethoxy imidate 11 obtained by reaction of 7 with ethyl chloroformate
• an arylhydrazine 12 or analog
• a tertiary amine such as triethylamine which effects cyclization to the triazolinone 13.
• Reaction Scheme I-20 A variation of Reaction Scheme I-20, shown in Reaction Scheme I-21, has been described by P. Gold-Aubert, D. Melkonian, and L. Toribio, Helv. Chim. Acta, 47, 1188 (1964) and A. L. Langis, U.S. Pat. No. 3,499,000 (1970).
• the readily prepared acylurea 19 upon heating with an arylhydrazine 12 (at about 150°-200° C.) is converted to the triazolinone intermediate 13.
• 2,4,5-Trisubstituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones (2,4,5-trisubstituted-1,2,4-triazolin-3(4H)-thiones) cannot generally be prepared by routes analogous to those in Reaction Schemes I-17 to I-22 because of the propensity for alkylation to occur on sulfur rather than on the open ring nitrogen. It is thus preferable to have all of the substituents in place at the time of the ring closure to form the heterocycle.
• reaction of the hydrazine derivative 23 with the appropriate isocyanate or isothiocyanate 22 yields the 2,4-disubstituted semicarbazide or thiosemicarbazide 24.
• Acylation of 24 gives 25, which can be cyclized upon heating with hydroxide or alkoxide to give the trisubstituted triazolinone or triazolinethione 26.
• This approach has been detailed by J. M. Kane and F. P. Miller, U.S. Pat. No. 4,775,688 (1988) and G. F. Duffin, J. D. Kendall, and H. R. J. Waddington, J. Chem. Soc., 3799 (1959).
• Alternative methods of ring closure, such as heating 24 with the orthoester 27, can also be utilized.
• Reaction Scheme I-28 utilizes chemistry reported by E. Akerblom, Acta Chem., Scand., 19, 1135 (1965).
• the substituted isothiourea 43 is treated with amine 10 to give the aminoguanidine derivative 44.
• Acylation of 44 with the acid chloride 16 provides the intermediate 45, which can be cyclized by heating the hydroxide or alkoxide.
• the desired triazolinimine 46 is separated from the isomeric product 47.
• Scheme I-30 provides the method by which the isomer (wherein K 2 is --C(O)--) 2,3,5, and 6-substituted pyrimidinones may be synthesized.
• a ⁇ -carbonyl ester is converted into its corresponding ⁇ -aminocrotonate with ammonia.
• This is then acrylated with an R 1 -containing acyl chloride (R 1 COCl) and cyclized to a 3.1-oxazin-4-one.
• R 1 COCl an R 1 -containing acyl chloride
• Scheme I-31 shows how an R 6 imidate may be converted to an amidine with the substituted benzylamine, followed by treatment with an appropriately substituted ⁇ -carbonyl ester to give the desired pyrimidinone 4. 5 ##STR54##
• Scheme I-33 illustrates the general synthesis of pyrimidinones of Formula Ic in which B is a sulfur atom.
• Thiourea when condensed with a ⁇ -carbonyl ester gives the 2-thiouracil.
• This can be bis-trimethylsilylated using hexamethyldisilazane, then alkylated sequentially on the 1-nitrogen atom and then on the sulfur atom using chemistry developed by H. Vorbruggen and P. Strehlke. 6
• J 2 is --C(O)-- and B is a sulfur atom.
• the isomeric 2,3-dialkylated thiouracils may be synthesized as shown in Scheme I-34.
• Thiourea can be condensed with an appropriately substituted ⁇ -carbonyl ester to give the 5,6-disubstituted-2-thiouracil.
• 7 This may then be alkylated sequentially at the sulfur with an R 1 halide, and then at the nitrogen atom with an appropriately substituted alkyl halide to give the desired tetrasubstituted pyrimidinone 4.
• R 1 halide an appropriately substituted alkyl halide
• an isothiocyanate can be converted into a thiourea by the addition of ammonia. 8 This can then be condensed with the appropriately substituted ⁇ -carbonyl ester to give the 3,5,6-trisubstituted-2-thiouracil. 9 Alkylation at the sulfur atom with base and an R 1 halide then gives the desired pyrimidinone 4. ##STR58##
• Scheme I-36 provides a method by which the 2-alkoxy-1-alkylpyrimidinones may be synthesized.
• An appropriately substituted ⁇ -keto amide 10 is cyclized with carbonyl diimidazole 11 and converted to the corresponding uracil upon treatment with the appropriately substituted primary amine.
• the uracil can then be converted to the 2-alkoxy-1-alkylpyrimidinone by treatment with an R 1 orthoester.
• Scheme I-37 shows how the methods of Wittenburg 14 might be employed to accomplish the same transformation. ##STR59##
• Scheme I-38 shows how the isomeric 2-alkoxy-3-alkylpyrimidinones can be prepared.
• the primary amine can be converted into an isocyanate 15 , then converted to the corresponding urea by treatment with ammonia. Reaction of the urea with an appropriately substituted ⁇ -keto ester then gives the 3-substituted uracil. 16 Conversion of the uracil to the corresponding 2-alkoxy pyrimidinone is achieved using an R 1 orthoester. 17 Alternatively, a ⁇ -aminocrotonate can be reacted with the isocyanate, as shown in Scheme I-39 18 , then alkoxylated with an R 1 orthoester.
• R 17 may be alkyl or aryl. Alkylation of this material with an alkyl halide (R 18 -Q) is achieved using sodium hydride in DMSO or by other classical methods. R 18 may be alkyl or aralkyl suitable protected, if necessary, so as not to react with NaH.
• Scheme I-41 illustrates the preparation of the 5-alkoxycarbonyl moiety and the corresponding 5-amino derivatives. ##STR60##
• the nitrile is converted to the trityl protected tetrazole in a three step procedure using trimethyltin azide in refluxing toluene followed by treatment with acid and finally protection with triphenylmethyl chloride in the presence of triethyl amine using CH 2 Cl 2 or CHCl 3 as solvent.
• the protected tetrazole compound can be treated with N-bromosuccinimidein refluxing carbontetrachloride in the presence of a catalytic amount of AIBN or benzoylperoxide to provide the necessary bromoethylphenyl thiophenes.
• the dianion is generated with two equivalents of a strong base such as nBuLi or tBuLi; this is followed by quenching with TMSCl, addition of another equivalent of strong base and finally quenching with Br 2 .
• a strong base such as nBuLi or tBuLi
• TMSCl quenching with TMSCl
• Br 2 quenching with Br 2 .
• These bromo derivatives are coupled with p-tolyltrimethyl tin in the presence of a catalytic amount of palladium (0) in refluxing toluene or hot DMF.
• Benzylic bromination using N-bromosuccinimide provides the desired bromomethylphenyl thiophenes and bromomethylphenyl furans.
• the desired antagonists of formula I are prepared, as illustrated in scheme II-8, by deprotonation of the desired heterocycle, for example 2 -butyl-6-methylquinazolin-4(1H)-one, with sodium hydride in dimethylformamide to generate the sodium salt, 8a. Alkylation of the sodium salt with a derivative containing a good leaving group such as the bromomethyl derivative or the methanesulfonyl derivative, is followed by deprotection to provide the free tetrazole.
• the desired heterocycle for example 2 -butyl-6-methylquinazolin-4(1H)-one
• the desired antagonists of formula I (Z ⁇ SO 2 NHCOR 7 ) are prepared, as illustrated in scheme II-9, by deprotonation of the desired heterocycle, for example 2-butyl-6-methylquinazolin-4-(1H)-one, with sodium hydride in dimethylformamide to generate the sodium salt. Alkylation of the sodium salt with the bromomethyl derivative or the methanesulfonyl derivative followed by deprotection with trifluoroacetic acid and coupling with an activated acid derivative completes the synthesis of the sulfonamide containing thiophene antagonists.
• the desired heterocycle for example 2-butyl-6-methylquinazolin-4-(1H)-one
• the desired antagonist of formula I where X 1 --X 2 --X 3 --X 4 ⁇ --CR 11 --CR 12 --S--CZ--, Z ⁇ SO 2 HNCOR 7 , R 11 and R 12 are joined to form an aryl ring, and R 7 ⁇ Ph, is prepared as illustrated in scheme II-10 by deprotonation of the desired heterocycle, for example 2-butyl-6-methylquinazolin-4(1H)-one, with sodium hydride in dimethyl formamide to generate the sodium salt. Alkylation of the sodium salt with the benzothiophene derivative, compound 4e, which is prepared using the chemistry illustrated in scheme II-4, affords 10a. As in scheme II-9, deprotection with TFA is followed by coupling to an activated acid derivative to complete the synthesis. ##STR68##
• This benzyl bromide is used in place of compound 2d in scheme II-9 to complete the synthesis of the antagonist.
• Scheme II-12 illustrates a more convergent approach to the synthesis of substituted thiophenes of formula I, where X 1 --X 2 --X 3 --X 4 ⁇ --CH ⁇ C(R 12 )--S--CZ ⁇ and Z ⁇ SO 2 HNCOR 14 .
• Palladium catalyzed coupling of boronic acid 11b with a 4-bromobenzyl derivative, such as 12a provides a nearly complete antagonist.
• Completion of the antagonist from 12b is illustrated in scheme II-9. ##STR69##
• alkylthiophene 13a is prepared by alkylation of the 2-(triphenylmentyltetrazolyl)-thiophene with an appropriate alkylhalide (R 12 X). Directed metallation with BuLi, is followed by quenching with triisopropylborate. The borate ester is gently hydrolyzed with dilute acetic acid to afford the boronic acid derivative 13b.
• This benzyl bromide is used in place of compound 2d in scheme II-9 to complete the synthesis of the antagonist.
• Palladium catalyzed coupling of boronic acid 13b with a 4-bromobenzyl derivative, such as 12a provides a nearly complete antagonist.
• Completion of the antagonist from 14b is illustrated in scheme II-9. ##STR70##
• Benzylic bromination is followed by coupling to the sodium salt of a heterocycle such as a substituted quinazolinone, triazolinone or pyrimidinone to afford 15e.
• Reductive amination of the aldehyde is then followed by the usual reactions to complete the synthesis of the antagonist.
• bromomethyl derivative 16e (scheme II-16) can be prepared and coupled to a heterocycle using previously described synthetic methods.
• NBS bromination of 2-methyl-5-(tbutylsulfonamido)thiophene provides bromomethyl derivative 16a.
• the bromomethyl derivative is then reacted with excess amine (HNR 2a R 2a ), such as morpholine, to afford 16b.
• Reaction of 16b with two equivalents of a strong base, such as LDA or nBuLi is followed by addition of bromine to provide 16c.
• Palladium catalyzed coupling of 16c with 4-(t-butyldimethylsilyloxymethyl)-phenyltrimethyltin provides compound 16d. Silyl removal followed by conversion to the corresponding bromide affords 16e. ##STR71##
• Antagonists of formula I, where the heterocycle is a 2-alkyl-8-nitrogen substituted quinazoline-4(1H)-one, X 1 --X 2 --X 3 --X 4 is --CH ⁇ CR 12 --S--CZ ⁇ , and Z ⁇ SO 2 NHCOR 14 are best prepared by the synthetic route outline in Scheme II-17. Hydrogenation of the 6-nitroquinazolinone cleanly produces the desired amino derivative. Acylation with an appropriate acid chloride in the presence of pyridine provided derivative 17c. Coupling of 17c with lid in DMF using K 2 CO 3 affords the coupled product 17d. Deprotection with TFA is followed by acylation, with either and acid chloride (R 14 COCl) in the presence of pyridine or an acid (R 14 CO 2 H) after prior activation with CDI, to complete the antagonist. ##STR72##
• the compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention.
• Such salts include ammonium salts, alkali metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases; e.g., dicyclohexylamine salts, N-methyl-D-glucamine, salts with amino acids like arginine, lysine, and the like.
• salts with organic and inorganic acids may be prepared; e.g., HCl, HBr, H 2 SO 4 , H 3 PO 4 , methane-sulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic.
• the non-toxic, physiologically, acceptable salts are preferred, although other salts are also useful; e.g., in isolating or purifying the product.
• the salts can be formed by conventional means such as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.
• AII Angiotensin II
• the compounds described in the present invention act as competitive antagonists of AII at the receptors.
• the following two ligand-receptor binding assays were established.

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